Angiopoietin-Like Protein 8 Is a Novel Vitamin D Receptor Target Gene Involved in Nonalcoholic Fatty Liver Pathogenesis

García‐Monzón, Carmelo; Petrov, Petar; Rey, Esther; Marañón, Patricia; Pozo-Maroto, Elvira Del; Guzmán, Carla; Cía, Javier Rodríguez de; Casado-Collado, Alfonso J.; Vargas-Castrillón, Javier; Saez, Alicia; Miquilena-Colina, María E.; Iacono, Oreste Lo; Castell, José V.; González-Rodrı́guez, Águeda; Jover, Ramiro

doi:10.1016/j.ajpath.2018.07.028

Cited by 33 publications

(35 citation statements)

References 34 publications

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“…We also searched for gene candidates involved in this VDR-dependent effect and found some lipid metabolism genes (e.g., DGAT2 or CEBPA) that responded to plasmid-transfected VDR in HepG2 [9]. Another uncovered VDR-target gene involved in lipid metabolism was ANGPTL8 [8]. In the present study, we performed whole transcriptome analysis after VDR activation in human hepatocytes to identify the whole repertoire of potential VDR-dependent lipid metabolism genes.…”

Section: Discussionmentioning

confidence: 94%

“…All the other detected genes showed higher expression in the VitD-supplemented mice, supporting the notion that they could be novel positive VDR target genes in vivo (Figure 4). ANGPTL8, another VDR target gene involved in TG homeostasis [8], was repressed by 70% in the livers of apoE & Vdr double knock-out mice vs. apoE −/− mice (data not shown).…”

Section: Expression and Regulation Of Novel Vdr-responsive Genes In Mmentioning

confidence: 97%

“…More recently, we have also proposed a new link between VDR and hepatic lipid metabolism as VDR deletion protected apoE -/mice from HFD-induced liver steatosis, which led us to postulate that hepatocyte VDR could play a key role in liver lipid metabolism and NAFLD pathogenesis [9]. In this context, we have also uncovered ANGPTL8 as a novel VDR target gene that potentially contributes to higher triglyceride (TG) levels [8].…”

Section: Introductionmentioning

confidence: 93%

“…Cells were incubated with a non-cytotoxic dose of 1 plaque-forming unit/cell of adenoviral vectors: Ad-VDR, encoding human VDR, or Ad-C, an insertless adenovirus. This dose of Ad-VDR increases VDR expression to levels comparable to those found in NAFLD livers [8,9]. Forty-eight hours later, cells were shifted to adenovirus-free medium and cultured for an additional period of time in the presence of VDR agonists: VitD (1a,25-dihydroxyvitamin D3/calcitriol, Sigma Aldrich, Madrid, Spain) or LCA (lithocholic acid, Sigma Aldrich, Madrid, Spain).…”

Section: Culture Of Human Upcyte Hepatocytes and Hepg2 Cellsmentioning

confidence: 99%

“…Nevertheless, VDR mRNA and protein are expressed in human hepatocytes and HepG2 cells [4], where several typical hepatocyte genes are regulated by VitD via functional VDR response elements [5,6], reinforcing the notion that VDR activation and signaling in hepatocytes is also important. On top of that, hepatocyte VDR levels are induced by several conditions and stimuli: in human HepG2 cells, VDR expression is upregulated by free fatty acids, insulin, lithocholic acid (LCA), and VitD [4,7,8], and in human and mouse livers (e.g., apoE -/mice on high-fat diet (HFD) or mice on methionine-choline deficient diet) VDR is significantly induced in the settings of non-alcoholic fatty liver disease (NAFLD) [9].…”

Section: Introductionmentioning

confidence: 99%

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The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

et al. 2020

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The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4–6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids.

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Section: Discussionmentioning

confidence: 94%

Section: Expression and Regulation Of Novel Vdr-responsive Genes In Mmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 93%

Section: Culture Of Human Upcyte Hepatocytes and Hepg2 Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

et al. 2020

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Effects of liposoluble components of highland barley spent grains on physiological indexes, intestinal microorganisms, and the liver transcriptome in mice fed a high‐fat diet

Zhang

Luo

Feng

et al. 2023

Food Science & Nutrition

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The purpose of this study was to investigate the effects of the active ingredients of barley lees on the physiological indexes, intestinal flora, and liver transcriptome of mice fed a high‐fat diet. Twenty‐four male C57BL/6J mice were randomly divided into 4 groups and fed the experimental diets for 5 weeks. The results showed that the fat‐soluble components of distillers' grains significantly reduced body weight, abdominal fat, perirenal fat, blood glucose, low‐density lipoprotein cholesterol, triglycerides, and total cholesterol in the high‐fat diet‐fed mice (p < .05), significantly decreased alanine aminotransferase and malondialdehyde levels, and significantly increased total superoxide dismutase, catalase, reduced glutathione and glutathione peroxidase levels (p < .05). At the phylum level, lipid‐soluble components significantly increased the abundance of Bacteroidetes and decreased the Firmicutes/Bacteroidetes ratio. At the genus level, the relative abundances of Bacteroidetes and Clostridium were increased. Transcriptomic analysis showed that lipid‐soluble components of spent grains reduced the mRNA expression of ANGPTL8, CD36, PLTP, and SOAT1 and increased the mRNA expression of CYP7A1 and ABCA1 in the cholesterol metabolism pathway, promoted the transport of cholesterol, and inhibited the absorption of cholesterol, which can decrease cholesterol levels by speeding up the conversion of cholesterol into bile acids.

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Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes

et al. 2020

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Angiopoietin-Like Protein 8 Is a Novel Vitamin D Receptor Target Gene Involved in Nonalcoholic Fatty Liver Pathogenesis

Cited by 33 publications

References 34 publications

The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

Effects of liposoluble components of highland barley spent grains on physiological indexes, intestinal microorganisms, and the liver transcriptome in mice fed a high‐fat diet

Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes

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